1. Field of the Invention
This invention relates to compounds and pharmaceutical compositions comprising such compounds which inhibit cellular .beta.-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease.
2. References
The following publications, patents and patent applications are cited in this application as superscript numbers:
1 Glenner, et al., "Alzheimer's Disease: Initial Report of the Purification and Characterization of a Novel Cerebrovascular Amyloid Protein", Biochem. Biophys. Res. Commun., 120:885-890 (1984). PA1 2 Glenner, et al., "Polypeptide Marker for Alzheimer's Disease and its Use for Diagnosis", U.S. Pat. No. 4,666,829 issued May 19, 1987. PA1 3 Selkoe, "The Molecular Pathology of Alzheimer's Disease", Neuron, 487-498 (1991). PA1 4 Goate, et al., "Segregation of a Missense Mutation in the Aryloid Precursor Protein Gene with Familial Alzheimer's Disease", Nature, 342:704-706 (1990). PA1 5 Chartier-Harlan, et al., "Early-Onset Alzheimer's Disease Caused by Mutations at Codon 717 of the .beta.-Amyloid Precursor Proteing Gene", Nature, 353:844-846 (1989). PA1 6 Murrell, et al., "A Mutation in the Amyloid Precursor Protein Associated with Hereditary Alzheimer's Disease", Science, 254:97-99(1991). PA1 7 Mullan, et al., "A Pathogenic Mutation for Probable Alzheimer's Disease in the APP Gene at the N-Terminus of .beta.-Aryloid, Nature Genet., 1:345-347 (1992). PA1 8 Schenk, et al., "Methods and Compositions for the Detection of Soluble .beta.-Amyloid Peptide", International Patent Application Publication No. WO 94110569, published May 11, 1994. PA1 9 Selkoe, "Amyloid Protein and Alzheimer's Disease", Scientific American, pp. 2-8, November, 1991. PA1 10 Losse, et al., Tetrahedron, 27:1423-1434 (1971). PA1 11 Citron, et al., "Mutation of the .beta.-Amyloid Precursor Protein in Familial Alzheimer's Disease Increases .beta.-Protein Production, Nature, 360:672-674 (1992). PA1 12 Hansen, et al., "Reexamination and Further Development of a Precise and Rapid Dye Method for Measuring Cell Growth/Cell Kill", J. Immun. Meth., 119:203-210 (1989). PA1 13 P. Seubert, Nature (1992) 359:325-327 PA1 14 Johnson-Wood et al., PNAS USA (1997) 94:1550-1555 PA1 15 Tetrahedron Letters, 34(48), 7685 (1993)) PA1 wherein R.sup.1 is selected from the group consisting of: PA1 R.sup.2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; PA1 each R.sup.4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl; PA1 each R.sup.5 is selected from hydrogen and methyl or together with R.sup.4 forms a cycloalkyl group of from 3 to 6 carbon atoms; PA1 X is --C(O)Y or --C(S)Y where Y is selected from the group consisting of PA1 X can also be --CR.sup.6 R.sup.6 Y' where each R.sup.6 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, phthalimido, --OC(O)R.sup.7, --SSR.sup.7, --SSC(O)R.sup.7 where R.sup.7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, PA1 X' is hydrogen, hydroxy or fluoro; PA1 X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group, and PA1 n is an integer equal to 1 or 2; PA1 with the proviso excluding the following known compound: PA1 R.sup.2 is selected from the group consisting of PA1 each R.sup.4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl; PA1 each R.sup.5 is selected from hydrogen and methyl or together with R.sup.4 forms a cycloalkyl group of from 3 to 6 carbon atoms; PA1 X is --C(O)Y or --C(S)Y where Y is selected from the group consisting of PA1 X can also be --CR.sup.6 R.sup.6 Y' where each R.sup.6 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, substituted alkoxy, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, phthaliimido, --OC(O)R.sup.7, --SSR.sup.7, --SSC(O)R.sup.7 where R.sup.7 is selected from the group consisting of alyl, substituted alkyl, cycloakyl, aryl, heteroaryl and heterocyclic, PA1 X' is hydrogen, hydroxy or fluoro; PA1 X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group, and PA1 n is an integer equal to 1 or 2; ##STR3## PA1 wherein R.sup.1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; PA1 R.sup.2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; PA1 R.sup.4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl provided that at least one R.sup.4 is selected to be: PA1 each R.sup.5 is selected from hydrogen and methyl or together with R.sup.4 forms a cycloalkyl group of from 3 to 6 carbon atoms; PA1 X is --C(O)Y or --C(S)Y where Y is selected from the group consisting of PA1 X can also be --CR.sup.6 R.sup.6 Y' where each R.sup.6 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, substituted alkoxy, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, phthalimido, --OC(O)R.sup.7, --SSR.sup.7, --SSC(O)R.sup.7 where R.sup.7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, PA1 X' is hydrogen, hydroxy or fluoro; PA1 X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group, and PA1 n is an integer equal to 1 or 2; and ##STR4## PA1 wherein R.sup.1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; PA1 R.sup.2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; PA1 each R.sup.4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl; PA1 each R.sup.5 is selected from hydrogen and methyl or together with R.sup.4 forms a cycloalkyl group of from 3 to 6 carbon atoms; PA1 X is selected from the group consisting of PA1 X can also be --CR.sup.6 R.sup.6 Y' where each R.sup.6 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of amino, thiol, alkoxy, phthalimido, --OC(O)R.sup.7, --SSR.sup.7, --SSC(O)R.sup.7 where R.sup.7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, PA1 provided that R' and R" are not both independently selected from hydrogen, alkyl, phenyl, benzyl and phenethyl; PA1 X' is hydrogen, hydroxy or fluoro; PA1 X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group, and PA1 n is an integer equal to 1 or 2; PA1 with the proviso that: PA1 with the additional provisos that in compounds selected from formulas I-IV: PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-histidine methyl ester PA1 N-benzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide PA1 N-2-(N,N-dimethylamino)ethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-( S)-2-aminohexanamide PA1 N-(2-methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino hexanamide PA1 N-2-(N,N-dimethylamino)ethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L -phenylalaninamide PA1 N-(4-pyridyl)methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylal aninamide PA1 N-(3-pyridyl)methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylal aninamide PA1 N-(4-pyridyl)methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amin ohexanamide PA1 N[-N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate tert-butyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-[3-(N,N-dimethylamino)propo xy]phenylalanine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl-L-4-[(tert-butyloxycarbonyl)meth oxy]phenylalanine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl-L-4-(carboxymethoxy)phenylalanin e methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(2-morpholinoethoxy)phenyla lanine methyl ester PA1 N-N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-6-(N,N-dimethylamino )hexanoate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-pyridyl)propio nate methyl ester PA1 N[-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(3-pyridyl)propiona te methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3(4-pyridyl)propion ate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionate methyl ester PA1 N-[N-(3,5-difluorphenylacetyl)-L-alaninyl]-2-amino-3-morpholinopropionate methyl ester PA1 N-(2-methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(2-morp holinoethoxy)phenylalaninamide PA1 N-(2-methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-m ethoxypropionamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine methyl ester PA1 N-(2-methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-( 4-pyridyl)propionamide PA1 N-(2-methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-( 2-pyridyl)propionamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazol-4-yl)pro pionate methyl ester PA1 N-(3-methoxybenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylal aninamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-naphthyl)propi onate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-naphthyl)propi onate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-thienyl)propio nate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine benzyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine 3-bromo-propyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine 3-iodopropyl ester PA1 N-N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-leucine tert-butyl ester PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-N.sub..epsilon. -(tert-butoxycarbonyl)-L-lysine methyl ester PA1 methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-4-phenylbutanoate PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine 2-phenylethyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine 3-phenylpropyl ester PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-pyridyl)acetamide PA1 N-[N-(3,5 difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetate ethyl ester PA1 N-methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide PA1 N,N-dimethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexana mide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-anion-2-(3-methoxyphenyl)acet ate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-methoxyphenyl)acet ate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetate ethyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-pyridyl)acetate ethyl ester PA1 N-[N-(cyclohex-1-enylacetyl)-L-alaninyl]-L-phenylalanine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-1-aminocyclopropane-1-carboxyla te methyl ester PA1 N-2-(N,N-dimethylamino)ethyl-N-methyl-N'-[N-(3,5-difluorophenylacetyl)-L-al aninyl]-L-alaninanide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl ester PA1 N-hydroxy-N'-[N-(3-nitrophenylacetyl)-L-alaninyl]-D,L-threoninarmide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide PA1 N-methoxy-N-methyl-N'-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninamide PA1 N-iso-butyl-N'[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide PA1 N,N-di-n-propyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valinamide PA1 N'-(4-nitrophenyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninami de PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide PA1 N-(2-methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylala ninamide PA1 N-(4-nitrobenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamid e PA1 N-(4-nitrophenyl)-N'-[N-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-ala ninamide PA1 N-(4-nitrophenyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalan inamide PA1 N-benzyl-N-methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamid e PA1 N-(3,5-difluorobenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alani namide PA1 N-(3-nitrobenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamid e PA1 N-benzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide PA1 N-(4-nitrobenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalan inamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tryptophan methyl ester PA1 N-(4-methoxybenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninam ide PA1 N-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninyl]-L-phenylgl ycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine methyl ester PA1 N-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl3-L-phenylglycine methyl ester PA1 N-(2-phenylethyl)-N'-[N-(3,5-difluoropbenylacetyl)-L-alaninyl]-L-alaninamid e PA1 N'-[N-(3,5-fluorophenylacetyl)-L-alaninyl]-L-tryptophanamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-cyclohexylpropion ate methyl ester PA1 N-(2-methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino -3-(4-nitrophenyl)propionamide PA1 N-[(R)-.alpha.-methylbenzyl]-N'-N-(3,5-difluorophenylacetyl)-L-alaninyl]-L- alaninamide PA1 N-[(S)-.alpha.-methylbenzyl]-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L -alaninamide PA1 N-(4-fluorobenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninami de PA1 N-(4-pyridylmethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninam ide PA1 N-(4-trifluoromethylbenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L- alaninamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-phenylpropionate ethyl ester PA1 N-[N-(3,5-fluorophenylacetyl)-L-alaninyl]-L-phenylalanine tert-butyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-methylpropionate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-cyclohexylacetate ethyl ester PA1 N-(2-methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylgly cinamide PA1 N-2-(N,N-dimethylamino)ethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L -phenylglycinamide PA1 N-(2-pyridylmethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylgl ycinamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-fluorophenyl)aceta te ethyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-fluorophenyl)aceta te ethyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-alanine ethyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-phthalimidopropionate ethyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine neopentyl ester PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinami de PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine tert-butyl ester PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide PA1 4-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valinyl]morpholine PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate methyl ester PA1 4-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-amino-3-tert-butoxybutyryl] morpholine PA1 4-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucinyl]morpholine PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-leucine methyl ester PA1 N-2-methoxyethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide PA1 N-2-(N,N-dimethylamino)ethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L -alaninamide PA1 N-cyclohexyl-N'-[N-3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide PA1 N-neopentyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide PA1 N-tetrahydrofurfuryl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanina mide PA1 N-2-pyridylmethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamid e PA1 3-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]thazolidine PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate methyl ester PA1 N-(R)-sec-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide PA1 1-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]pyrrolidine PA1 N-(S)-sec-butyl-N o[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valine methyl ester PA1 N-2-fluoroethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide PA1 N-[(S)-6-methyl-3-oxohept-2-yl]-N'(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-4-nitrobenzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobut yramide PA1 N-4-nitrobenzyl-N'-[N-(3,5-difluorophenyacetyl)-L-alaninyl]-(S)-2-aminopent anamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-fluorophenyl)aceta te methyl ester PA1 N'-[N-(3,5-diuorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetami de PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(5-chlorobenzothiophe n-2-yl)acetate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-2-yl)a cetate ethyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-3-yl)a cetate methyl ester PA1 N-[N-(3,5-fluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-thienyl)acetate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-5-yl)a cetate ethyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetat e methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetat e tert-butyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetic acid PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(1H-tetrazol-5-yl)ace tate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(6-methoxy-2-naph thyl)acetate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-trifluoromethylphe nyl)acetate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4,5,6,7-tetrahydrobe nzothiophen-2-yl)acetate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(thieno[2,3-b]thiophe n-2-yl)acetate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-methylthiazol-4-yl )acetate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohex-4-enoate methyl ester PA1 N-tert-butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(4- phenylphenyl)acetamide PA1 N-[N-(3,5-difluorophenylacetyl)-(S)-2-aminobutanoyl]-L-phenylglycine tert-Butyl Ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine tert-butyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-methionyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-leucinyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-phenylalaninyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)glycinyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycine methyl ester PA1 N-cyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinami de PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-lysine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-glutamide PA1 N-[(S)-3-hydroxy-6-methylhept-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alanina mide PA1 N-[(S)-2-hydroxy-1-phenyleth-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninam ide PA1 N-[N-(3,5-difluorophenyl-.alpha.-fluoroacetyl)-L-alaninyl]-L-phenylglycine tert-butyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-2-(S)-aminocyclohexylacetyl]-L-phenylglycin e methyl ester PA1 N-[(1 R,2S)-1-hydroxy-1-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alanina mide PA1 N-[(1R,2S)-1-hydroxy-1,2-diphenyleth-2-yl]-N'-(3,5-difluorophenylacetyl)-L- alaninamide PA1 N-[(1S,2R)-1-hydroxy-1-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-ala ninamide PA1 N-2-methoxyethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamide PA1 N-[(S)-2-hydroxy-1,2-diphenylethyl]-N'-(3,5-difluorophenylacetyl)-L-alanina mide PA1 N-[(S)-1-hydroxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-[.alpha.-hydroxy-.alpha.'-(4-hydroxyphenyl)-iso-propyl]-N'-(3,5-difluorop henylacetyl)-L-alaninamide PA1 N-2-pyridylmethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalan inamide PA1 N-[.alpha.-hydroxy-.alpha.'-pyrid-2-yl-iso-propyl]-N'-(3,5-difluorophenylac etyl)-L-alaninamide PA1 N-[.alpha.-hydroxy-.alpha.'-pyrid-4-yl-iso-propyl]-N'-(3,5-difluorophenylac etyl)-L-alaninamide PA1 N-[(S)-1-hydroxy-4-methylpent-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alanina mide PA1 N-[.alpha.-methoxy-prop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-[1-hydroxy-3-methyl-but-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(6-aminopyrid-2-yl)ac etate methyl ester PA1 N-[1-hydroxy-prop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-[(S)-2-methoxy-1-phenyleth-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninam ide PA1 N-[(S)-1-methoxy-2-phenyl-prop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alanin amide PA1 N-[(S)-1-acetoxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-[(S)-1-(tert-butylcarbonyloxy)-hex-2-yl]-N'-(3,5-difluorophenylacetyl)-L- alaninamide PA1 N-[2-hydroxy-1-(thien-2-yl)ethyl]-N'-(3,5-difluorophenylacetyl)-L-alaninami de PA1 N-[(S)-2-hydroxy-2-methyl-1-phenylprop-1-yl]-N'-(3,5-difluorophenylacetyl)- L-alaninamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-(thien-2-yl)glycinyl]-L-phenylalanine tert-butyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinol PA1 N-[N-(3,5-difluorophenylacetyl)-D,L-phenylglycinyl]-D,L-phenylglycinamide PA1 N-[N-(3,5-difluorophenylacetyl)-D,L-valinyl]-D,L-phenylglycinamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-norleucinyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-tert-leucinyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-isoleucinyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-cyclohexylalaninyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(cyclopropyl)acetyl]-L-phenyl glycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(thien-3-yl)acetyl]-L-phenylg lycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(thien-2-yl)acetyl]-L-phenylg lycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-(4-fluorophenyl)glycinyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-D-(4-fluorophenyl)glycinyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-(4-methoxyphenyl)glycinyl]-L-phenylglycin e methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycine tert-butyl ester PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(5-bromothien-2 -yl)glycinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(5-bromothien-2 -yl)glycinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-bromothien-2 -yl)glycinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(thien-2-yl)gly cinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)gly cinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(thien-3-yl)gly cinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-3-yl)gly cinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycinami de PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinami de PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(5-chlorothie n-2-yl)glycinamide PA1 N-Cyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-4-(phenyl)pheny lglycinamide PA1 N-tert-butyl-N'-[N-(3,5-fluorophenylacetyl)-L-alaninyl]-L-3-(phenoxy)phenyl glycinamide PA1 N-(S)-(-)-.alpha.-methylbenzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl] -D,L-phenylglycinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-3-(phenyl)pheny lglycinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(ethyl)phenyl glycinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-(phenyl)pheny lglycinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-(benzyl)pheny lglycinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-bromophenyl glycinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(cyclohexyl)p henylglycinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(4-ethylpheny l)phenylglycinamide PA1 N-tert-butyl-N'-[N-(3,5-fluorophenylacetyl)-L-alaninyl]-D,L-4-(tert-butyl)p henylglycinamide PA1 N-tert-butyl-N'-[N-(3,5-fluorophenylacetyl)-L-alaninyl]-D,L-3-(4-chlorophen oxy)phenylglycinamide PA1 N-cyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(phenyl)pheny lglycinamide PA1 N-[N-(3,5-difluorophenyl-.alpha.,.alpha.-hydroxyacetyl)-L-alaninyl]-L-pheny lglycine tert-butyl ester PA1 N-tert-butyl-N '[N-(3,5-difluorophenyl-a,.alpha.-difluoroacetyl)-L-alaninyl]-L-phenylglyc inamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine tert-butyl ester PA1 N-[(S)-1-oxo-1-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-[N-(3,5-fluorophenylacetyl)-L-alaninyl]-D,L-(pyrid-3-yl)glycine tert-butyl ester PA1 [N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyl]morpholine PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(2-methoxy)phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine N-tert-butoxycarbonyl(hydroxyl amine) ester PA1 N-neopentyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinam ide PA1 N-tetrahydrofurfuryl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-pheny lglycinamide PA1 N-methoxy-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamid e PA1 [N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyl]azetidine PA1 N-iso-butyl-N'-[N(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinami de PA1 N-cyclopropanemethyl-N'-[N-(3,5-difluorophenylacetyl) L-alaninyl]-D,L-phenylglycinamnide PA1 N-methoxy-N-methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylg lycinamide PA1 N-2-methylprop-2-enyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phen ylglycinamide PA1 N-(pyrid-3-yl)methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-pheny lglycinamide PA1 N-(pyrid-4yl)methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenyl glycinamide PA1 N-furfuryl-N'-[N-(3,5-difluorhenylacetyl)-L-alaninyl]-D,L-phenylglycinamide PA1 N-cyclopentyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycin amide PA1 N-1-benylpiperidin-4-yl-N'-[N-(3,5-difluorophenylactyl)-L-alaninyl]-D,L-phe nylglycinamide PA1 N,N-dimethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycina mide PA1 N-2,2,6,6-tetramethylpiperidin-4-yl-N'-[N-(3,5-difluorophenylacetyl)-L-alan inyl]-D,L-phenylglycinamide PA1 N-2-methylcyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-pheny lglycinamide PA1 N-4-methylcyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-pheny lglycinamide PA1 N-1-ethoxycarbonylpiperidin-4-yl-N'-[N-(3,5-difluorophenylacetyl)-L-alaniny l]-D,L-phenylglycinamide PA1 N-methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide PA1 N-tert-butoxy-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycin amide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine N-tert-butyl(hydroxylamine) ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine hydrazide PA1 N-(1-ethoxyethen-1-yl)-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylg lycine hydrazide PA1 N-4-(phenyl)butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglyc inamide PA1 N-3-(4-iodophenoxy)propyl-N N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide PA1 N-6-(amino)hexyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylgly cinamide Hydrochloride PA1 N-1-(phthalimido)pent-2-yl-N'-(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-(3,5-difluorophenyl)glycinyl]-L-(3,5-difl uorophenyl)glycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-norleucine PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycine iso-propyl ester PA1 N-(isopropyl) N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine iso-butyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine methyl ester PA1 N-[N-(3,5-difluoropbenylacetyl)-L-alaninyl]-2-amino-2-(5-chlorobenzothiophe n-3-yl)acetate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazol-4-yl)pro pionate tert-butyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide tert-butyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamide PA1 N-[N-(3-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide PA1 N-[N-(4-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-furanyl)aceta mide PA1 N'-[N-(3,5-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamide PA1 N'-[N-(3,4-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanin-N-methylsulfona mide PA1 N"-methyl-N"-phenyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamid e PA1 N"-methyl-N"-phenyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninam ide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-phenylglycinamide PA1 N"-methyl-N"-benzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamid e PA1 N"-4-fluorobenzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglyc inamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-fluoro)phenylglycine neopentyl ester PA1 N-[N-(2,3,4,5,6-pentafluorophenylacetyl)-L-alaninyl]-L-(pyrid-3-yl)glycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(pyrid-3-yl)glycine tert-butyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-(O-benzyl)serinyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-(O-benzyl)threoninyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-tbreoninyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-serinyl]-L-phenylglycine methyl ester PA1 N"-4-methylphenyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglyc inamide PA1 N"-tetrahydrofurfuryl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenyl glycinamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenyl-glycinamide PA1 N'-[N-(3,5-difluorophenylacetyl-L-methionyl]-L-phenylglycinamide PA1 N-[N-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycinamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycinamide PA1 N-[(R)-.alpha.-methylbenzyl]-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L -phenylglycinamide PA1 N-[1-phenyl-2-oxo-3-methylbutan-1-yl]-N'(3,5-difluorophenylacetyl)-L-alanin amide PA1 N-[1-phenyl-2-oxo-propan-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-[1-phenyl-2-oxo-pentan-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-[1-phenyl-2-oxo-2-phenyl-ethan-1-yl]-N'-(3,5-difluorophenyl-acetyl)-L-ala ninamide PA1 N-[1-phenyl-2-oxo-butan-1-yl]-N'-(3,5-difluorophenyl-acetyl)-L-alaninamide PA1 N-[1-phenyl-2-oxo-4-methylpentan-1-yl]-N'-(3,5-difluorophenyl-acetyl)-L-ala ninamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-.alpha.-hydroxyphenylalanine methyl ester PA1 N"-[4-((2-hydroxy-4azido)-phenyl)NHC(O)-)butyl] N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide PA1 N-[(S)-1-phenyl-2-oxo-2-phenyl-ethan-1-yl]-N'(3,5-difluorophenyl-acetyl)-L- alaninamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycine tert-butyl ester PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-phenylphenylglycine tert-butyl ester PA1 N"-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-n-butylpheny lglycinamide PA1 N"-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-(phenylace tenyl)phenylglycinamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinthioamide PA1 N-[1,3-diphenyl-2-oxo-propan-1-yl]-N'(3,5-difluorophenylacetyl)-L-alaninami de PA1 N-[1-phenyl-2-oxo-2-cyclopentylethan-1-yl]-N'(3,5-difluorophenylacetyl)-L-a laninamide PA1 N-[1-phenyl-2-oxo-hexan-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-[1-phenyl-2-oxo-3-methylpentan-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alan inamide PA1 N"-n-hexyl-6-biotinamidyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L- phenylglycinthioamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-methionine PA1 N'-[N-(2-tert-BOC-amino)propionyl)-L-alaninyl]-L-phenylglycine methyl ester PA1 N"-tert-butyl N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-fluorophenylglycinamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-2-phenylglycine methyl ester PA1 N-[(S)-1-phenyl-2-oxo-3-phenylpropan-1-yl]-N'(3,5-difluorophenylacetyl)-L-a laninamide PA1 N'-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycin e PA1 N'-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycin e tert-butyl ester PA1 N'-[N-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl]-L-2-phenylglycine PA1 N'-N[N-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl]-L-2-phenylglycine tert-butyl ester PA1 N-[2-hydroxy-1-(S)phenyleth-1-yl]-N'-[(3,5-difluorophenylacetyl)-L-phenylgl ycinyl]-L-alaninamide PA1 N-[2-hydroxyeth-1-yl-N'-[(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylgly cinamide PA1 N'-[N-(3,5-difluorophenyl-2-oxo-acetyl)-L-alaninyl]-L-2-phenylglycine ten-butyl ester PA1 [N-(3-amioproprionyl)-L-alaninyl]-L-phenylglycine tert-butyl ester PA1 [N-3-tert-butoxycarbonylamio)propionyl)-L-alaninyl]-L-phenylglycine tert-butyl ester PA1 N-cyclohexyl-N-methyl-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D, L-phenylglycinamide PA1 N-cyclohexyl-N-methyl-N-[N-(3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-ala ninyl]-D,L-phenylglycinamide PA1 N-cyclohexyl-N'-[N-3,5-difluoropbenyl-.alpha.-hydroxyacetyl)-L-alaninyl]-D, L-phenylglycinamide.
All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
3. State of the Art
Alzheimer's Disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a very common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. AD has been observed in races and ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect about two to three million individuals in the United States alone. AD is at present incurable. No treatment that effectively prevents AD or reverses its symptoms and course is currently known.
The brains of individuals with AD exhibit characteristic lesions termed senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillary tangles. Large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. Smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of most aged humans who do not have clinical AD. Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D). At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.
The principal chemical constituent of the amyloid plaques and vascular amyloid deposits (amyloid angiopathy) characteristic of AD and the other disorders mentioned above is an approximately 4.2 kilodalton (kD) protein of about 39-43 amino acids designated the .beta.-amyloid peptide (.beta.AP) or sometimes A.beta., A.beta.P or .beta./A4. .beta.-Amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner, et al..sup.1 The isolation procedure and the sequence data for the first 28 amino acids are described in U.S. Pat. No. 4,666,829.sup.2.
Molecular biological and protein chemical analyses have shown that the .beta.-amyloid peptide is a small fragment of a much larger precursor protein (APP), that is normally produced by cells in many tissues of various animals, including humans. Knowledge of the structure of the gene encoding the APP has demonstrated that .beta.-amyloid peptide arises as a peptide fragment that is cleaved from APP by protease enzyme(s). The precise biochemical mechanism by which the .beta.-amyloid peptide fragment is cleaved from APP and subsequently deposited as amyloid plaques in the cerebral tissue and in the walls of the cerebral and meningeal blood vessels is currently unknown.
Several lines of evidence indicate that progressive cerebral deposition of .beta.-amyloid peptide plays a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, for example, Selkoe.sup.3. The most important line of evidence is the discovery that missense DNA mutations at amino acid 717 of the 770-amino acid isoform of APP can be found in affected members but not unaffected members of several families with a genetically determined (familial) form of AD (Goate, et al..sup.4 ; Chartier-Harlan, et al..sup.5 ; and Murrell, et al..sup.6) and is referred to as the Swedish variant. A double mutation changing lysine.sup.595 -methionine.sup.596 to asparagine.sup.595 -leucine.sup.596 (with reference to the 695 isoform) found in a Swedish family was reported in 1992 (Mullan, et al..sup.7). Genetic linkage analyses have demonstrated that these mutations, as well as certain other mutations in the APP gene, are the specific molecular cause of AD in the affected members of such families. In addition, a mutation at amino acid 693 of the 770-amino acid isoform of APP has been identified as the cause of the .beta.-amyloid peptide deposition disease, HCHWA-D, and a change from alanine to glycine at amino acid 692 appears to cause a phenotype that resembles AD is some patients but HCHWA-D in others. The discovery of these and other mutations in APP in genetically based cases of AD prove that alteration of APP and subsequent deposition of its .beta.-amyloid peptide fragment can cause AD.
Despite the progress which has been made in understanding the underlying mechanisms of AD and other .beta.-amyloid peptide related diseases, there remains a need to develop methods and compositions for treatment of the disease(s). Ideally, the treatment methods would advantageously be based on drugs which are capable of inhibiting .beta.-amyloid peptide release and/or its synthesis in vivo.